Cervical cancer is a cancer of the second highest incidence in females worldwide, and approximately 274,000 patients die from the disease every year. All cervical cancers can be detected with HPV infections. Additionally, anal, vaginal, penile, some of oral, and laryngeal cancers are also associated with HPV infections. Although there are so far two preventive vaccines having been put on the market, they are ineffective in treating the existing HPV infections, let alone in preventing the progression of lesion malignancy. And, it is estimated that there is already a very large population of patients infected with HPV. As a result, a large scale of preventive vaccination may require at least 20 years to substantially achieve a decreased incidence of cervical cancer. In view of the large population infected with the viruses who may even have developed a cervical cancer or a precancerous lesion, there is an urgent need of the development of a therapeutic vaccine for the purpose of cleaning up those cells and cancer cells that have been infected. HPV E6 and E7 proteins are oncoproteins encoded by two oncogenes carried by HPV viruses, belong to non-autologous, exogenous protein antigens, and persist with stable expression from precancerous lesions to the occurrence of cervical cancers, and thus are ideal targets for immunotherapy. Numerous clinical studies have attempted to target these two oncoproteins, including studies on recombinant viruses, polypeptides, proteins and DNA vaccines. These therapeutic vaccines exhibit excellent safety, and show degraded lesion and prolonged survival in some of the patients. Moreover, studies indicate that the degree of T cell immunity induced by vaccination may be associated with the therapeutic effect of the treatment. However, for the purpose of completely curing persistent infections and eliminating cancers, there is still a need of a new strategy for inducing a sufficient anti-tumor T cell immune response to a specific antigen, although there is already a prospect in some of the clinical studies.
Heat shock protein (HSP) can be effective in regulating cell function and enhancing immune responses. First, it can function as a “chaperone”, to assist protein transportation and positioning and protein folding; second, it can activate appropriative antigen presenting cells (APCs). HSP70 is capable of binding to a receptor on a macrophage, thereby effectively inducing an immune response thereof. SGN-00101 is a fusion protein fused with a E7 protein from HPV Type 16 and HSP65 from Mycobacterium tuberculosis, which has exhibited good safety and some effect on the inhibition of highly atypical proliferation in cervical epithelial cells.
Granulocyte-macrophage colony stimulating factor (GM-CSFs) has been widely studied and is recognized as one of the most effective therapeutic agents. It can mediate natural killer cells and activate CD8+ killer T lymphocytes specific to tumors through antigen presenting cells, so as to produce an anti-tumor effect. It has been demonstrated in many animal and clinical trials for the abilities to effectively stimulate tumor-suppressing immune response for a long period of time. For example, Sipuleucel-T, as an immunotherapeutic drug, is the one which takes advantage of the activation of antigen presenting cells with a GM-CSF, and now has been approved by U.S. Food and Drug Administration for marketing. The latest clinical study from Jennerex et al. also shows that oncolytic Vaccinia with an expression of a GM-CSF allows for a reduction of various cancer lesions. However, all of these immune enhancing methods have an unsatisfied therapeutic effect of either poor specificity to tumor antigen or insufficient immune stimulation.